The overall goal of this proposal is to develop and implement novel, multi-modal magnetic resonance imaging (MRI) in the human optic nerve capable of understanding the relationship between optic neuritis (ON) and the evolution of visual (dys)function and clinical evaluation. We further propose that quantitative MRI methods sensitive to tissue microstructure (myelin and axonal integrity) and biochemistry can be utilized in prediction models to offer insight into the eventual development of multiple sclerosis (MS). Recent studies have shown that optic neuritis is the initial symptom in 17-25% of all MS cases though visual function and inflammation generally resolves in 4 to 12 weeks. Additionally, nearly two thirds of MS patients will experience episodes of optic neuritis in their lifetimes, and 40-60% of MS patients have visual defects localized to the optic nerve. Ophthalmological and conventional MRI evaluation demonstrates inflammation along the optic nerve, but long- term prognosis has been challenging. We hypothesize the reason for this paradox is that conventional MRI is insensitive to tissue composition (axonal, myelin, or neurochemical) throughout the recovery course. While advanced MRI methods have been developed to assess large structures of central nervous system, relatively few have been applied in the optic nerve due to its size, location, and motion. However, recent innovations of MRI hardware and sequence design have yielded an opportunity to study new imaging modalities in the optic nerve. Importantly, these techniques offer unprecedented non-invasive access to the entire optic nerve with indices sensitive to axonal and myelin integrity, macro-molecular arrangement, and neurochemical composition. We hypothesize that characterizing the neurological substrates of optic nerve damage resulting from ON is critical for improving our understanding of the earliest relationships between ON and MS. Significantly, these tools may provide an opportunity for earlier intervention, and enhancing disease management. We have demonstrated the feasibility of new, non-invasive MRI approaches to quantitatively assess the optic nerve and we will integrate for the first time a set of tools that are sensitive to the microstructural integrit, myelination, and neurochemical composition of the optic nerve in patients with ON. We will utilize advanced statistical modeling to parse out the association of these MRI indices to visual function and the relationship to clinical and quantitative ophthalmological measures. Lastly we will build predictive models to determine the relationship between novel MRI measures and the personal risk of developing MS from a single ON event. In appreciation of a K01 which provided the opportunity to develop advanced MRI of the human optic nerve, we now possess a unique toolbox to assess the multiple neuropathological substrates of ON in a single MRI scanning session even after resolution of inflammation, which we hypothesize will offer insight into the temporal evolution of ON.